Dendritic cells (DCs) are powerful antigen presenting cells(APCs) that orchestrate various immune responses against specific antigens and at the same time suppress auto-immune response by deleting potentially autoreactive T cells. These apparently contradictory functions have been suggested to originate from different subsets of DCs.
Murine DCs can be subdivided into at least two distinct subtypes, myeloid and lymphoid DCs, on the basis of their anatomic localization, transplantation experiments, and cell surface phenotypes. DCs bearing the CD11c+, MHCII+, CD4+, CD8α− cell surface phenotype, called CD8α− myeloid DCs, can be derived from myeloid precursor cells, whereas DCs bearing the CD11c+, MHCII+, CD4−, CD8α+ cell surface phenotypes, called CD8α+ lymphoid DCs, are present in thymus or spleen.
It has been reported that murine CD8α+ lymphoid DCs also produce IFN-γ in response to IL-12 like NK cells(natural killer cells) and T cells (Toshiaki et al., Brief Definitive Report, 189(12), 1981-1986(1999)), Also, when lymphoid DCs such as murine Langerhans cells are injected into CD8α− mice, they are transferred into the lymph node and differentiate into CD8α+ DCs and the differentiated CD8α+ DCs can produce IFN-γ (Miriam et al., Blood, 96(5), 1865-1872(2000)).
Such lymphoid DCs not only induce immune tolerance but function as powerful immunogenic APCs against various allogeneic antigens, activating T helper cell type I response by producing IL-12 and IFN-γ.
DCs are present virtually in all tissues of the body, but in low concentrations, and it is therefore difficult and cumbersome to procure a sufficient amount of DCs for ex vivo manipulation.
Accordingly, various efforts have been made to generate DCs ex vivo from HSCs or monocytes in a large scale, using for example, several cytokines including Granulocyte-macrophae colony stimulating factor (GM-CSF), interleukin-4(IL-4), tumor necrosis factor-alpha (TNF-α) and stem cell factor (SCF). DCs which express CD1a+, CD4+, CD11c+, CD40+, CD54+, CD80+, CD83+, CD86+, HLA class I+, HLA class II+, CD3−, CD8− and CD14− were generated by using GM-CSF (Williams et al., Int. Rev. Cytol., 153: 412(1994); Santiago-Schwarz et al., Nature, 360: 258(1993); and Rosenzwajg et al., Blood, 87: 535(1996)).
However, it has never been reported that DCs of CD8α+ immunophenotype (CD8α+ DCs) are present in human or that CD8α+ DCs can be differentiated from human hematopoietic stem cells(HSCs).